The invention relates generally to nanoparticles, particularly those based on transition metal oxides, which have been treated with an α-hydroxy phosphonic acid derivative to render them sufficiently hydrophilic to form stable aqueous suspensions. The modified nanoparticles are useful in applications requiring hydrophilicity such as for use as therapeutic agents and as contrast agents in diagnostic imaging, for example, by magnetic resonance imaging (MRI).
In some applications, for example, when used as contrast agents or therapeutic agents, it is also desirable that the nanoparticles have a well defined reproducible structure and be amenable to safety testing. Accordingly, there has been a need for hydrophilic nanoparticles that do not suffer a degradation of their hydrophilicity as a result of purification and display suspension stability in aqueous mediums containing electrolytes. For instance, in the preparation of contrast agents for in vivo use in human subjects the candidate nanoparticles would typically be subjected to purification and be expected to show suspension stability in isotonic aqueous media, i.e. media containing about 150 mM NaCl. Efforts to enhance nanoparticle hydrophilicity and stability in saline by coating transition metal oxide particles with α-hydroxyphosphonic acid-PEG conjugates having molecular weights up to about 5,000 daltons have had some success.
To date, little if any information has been available regarding in vivo behavior of these modified particles. In particular, parameters related to residence time in the body are important to consider when nanoparticles are developed for use in diagnostic imaging, or if use as a therapeutic agent is contemplated. Residual MR signal from unprocessed iron oxide nanoparticles retains a strong MR signal, which is undesirable when repeat dosing of the agent is required in the clinical workflow. In that regard, the modified nanoparticles disclosed herein exhibit improved processing, such as in the liver, despite enhanced stability.